Farnesyltransferase inhibitors (FTIs) belong to a novel class of relatively non-toxic anti-cancer drugs that are currently being tested in clinical trials for a variety of cancers. Our studies have focused on exploring the utility of treating Ph-positive acute lymphoblastic leukemia (ALL) with FTIs. This type of leukemia is caused by the Bcr/Abl oncogenic fusion protein and has a very unfavorable prognosis. In the previous period of support, we showed that the FTI SCH66336 as monotherapy is extremely effective in preventing progression of pre-leukemia in a transgenic mouse model and can significantly prolong the life of mice with progressed disease and a very high tumor burden. However, drug resistance against this FTI could be readily induced both in vitro and in vivo and we identified several mechanisms that can contribute to this. Based on our preliminary data, we hypothesize, that the development of resistance of Bcr/Abl lymphoblastic leukemia cells to the FTI SCH66336 is facilitated by interactions between the microenvironment of the leukemic cells, which selects out a subpopulation of putative leukemia stem cells that is able to survive under the drug-restrictive conditions. To investigate this and to increase the efficacy of eradicating the malignant cells with FTI treatment, we propose the following Specific Aims. (1) To explore the expression and knockdown of the ABC transporter ATP11a in normal and malignant B-lineage cells and the effect of this on resistance to FTIs (2) To determine the effect of expression of the cell adhesion molecule N-cadherin in pre-B leukemia cells on their ability to resist treatment with FTIs (3) To define the characteristics of the minority subpopulations of lymphoblasts that derive protection from fibroblasts against FTI treatment and subsequently are able to grow out, including their sensitivity to other drugs with a presumed very different molecular target. Our experiments will provide important information on the mechanisms by which the Bcr/Abl expressing lymphoblasts acquire resistance to FTIs and will allow for a more optimal use of this class of drugs in the treatment of Ph-positive ALL, either as monotherapy or in combination with other drugs. FTIs belong to a novel, rapidly expanding class of promising anti-cancer drugs with relatively low toxicity. Because of this, our studies are very important in anticipating the problems that will emerge once these types of drugs are used on large numbers of human patients. Relevance: A major problem for patients who are treated with chemotherapy is that their cancer cells frequently stop responding to drug treatment. In the past 5 years there has been a spectacular development of new types of anti-cancer drugs that selectively target specific abnormal molecules in the cancer cells and that are relatively non-toxic. In anticipation of the future widespread use of such drugs to treat cancer, this project examines how cancer cells may develop resistance against these new drugs, using acute lymphoblastic leukemia and a drug (an FTI) as model.